Neuroinflammation in Autism Spectrum Disorders: Role of High Mobility Group Box 1 Protein

The pathogenesis of autism spectrum disorder (ASD) likely involves genetic and environmental factors, impacting the complex neurodevelopmental and behavioral abnormalities of the disorder. Scientific research studies emerging within the past two decades suggest that immune dysfunction and inflammation have pathogenic influences through different mechanisms, all leading to both a chronic state of low grade inflammation, and alterations in the central nervous system and immune response, respectively. The high mobility group box-1 protein (HMGB1) is an inflammatory marker which has been shown to play a role in inducing and influencing neuroinflammation. Current evidences suggest a possible role in the multiple pathogenic mechanisms of ASD. The aim of this manuscript is to review the major hypothesis for ASD pathogenesis, with specific regards to the immunological ones, and to provide a comprehensive review of the current data about the association between HMGB1 and ASD. A systematic search has been carried out through Medline via Pubmed to identify all original articles published in English, on the basis of the following keywords: “HMGB1”, “autism”, “autism spectrum disorder”, “neuroinflammation”, and “child”.

suggest that there are more environmental components than previously believed (8). Many environmental factors associated with the risk of ASD have been identified, and one candidate is the host inflammatory response (9). The aim of this manuscript is to review the major hypotheses for ASD pathogenesis, with specific regards to the immunological ones, and to provide a comprehensive review of the current data about the association between HMGB1 and ASD. A systematic search was carried out through Medline via Pubmed (https:// www.ncbi .nlm.nih. gov/ pubmed) to identify all original articles published in English, on the basis of the following keywords: "HMGB1", "autism", "autism spectrum disorder", "neuroinflammation", and "child".

Imunological dysfunction and inflammation in autism spectrum disorders
Both innate and adaptive branches of the immune system can impact neural development, cognitive functions, and behavioral pattern. From fetal development to adulthood, the immune system and central nervous system (CNS) interact with each other, influencing both systemic immune response (peripheral immune system) and local CNS immune function (the so-called 'neuroimmunity') (10). During fetal development, the activation of the maternal immune system may lead to changes in neural development; this is an important risk factor for ASD. Various interrelated factors may cause dysregulation of the maternal immune system. A study conducted by Zerbo et al. (11) found that maternal infectious diseases diagnosed at a hospital admission, especially bacterial ones, were related to increased risk of ASD. Infections during pregnancy, such as rubella (12)(13)(14) or influenza virus (15), can create an inflammatory immune environment and trigger the production of maternal cytokines and chemokines, which can not only affect directly the placenta but also may cross the placenta, and enter in the fetal compartment, exerting effects on the fetus development (10). These effects can also be achieved in the absence of active infection, via generalized inflammatory response or loss of immune regulation (16). Animal models of maternal immune activation (MIA) have been particularly significant in highlighting the importance of maternal immune regulation (16)(17)(18)(19)(20).
In addition, several studies have demonstrated that up to about 10% of mothers with ASD children and only 0-2% of controls have humoral antibodies against fetal brain proteins (10, 21-23). These antibrain auto-antibodies can likewise gain access to the developing fetal brain and bind to fetal proteins, thereby impairing the course of neurodevelopment.  receptor for advanced glycation end-products (RAGE) (53). HMGB1 is able to cross the bloodbrain barrier. The brain cells may therefore be exposed to HMGB1 released both in the brain and in the periphery, including the intestinal mucosa (47,54,55). Saresella et al. (56) showed that the inflammasome system is activated in ASD. They   (65), and it is believed that it may support a chronic low-grade inflammation and increased permeability of the intestinal wall, allowing inflammatory mediators to enter the circulation and likely cross the blood-brain barrier, hence influencing the brain function, including behavior (66,67).
Nowadays possible clinical targeting of HMGB1 is being explored. Treatment with inhibitors of HMGB1 activity has been proven efficacious in reducing the inflammatory activity in a broad range of preclinical disease models (68).

Conclusion
In summary, increased HMGB1 levels have More larger-scale studies are needed to be performed to clarify the role of HMGB1 in the pathogenesis of autism spectrum disorder, potentially leading to novel disease markers and targeted therapeutics.